DE4131562A1 - SOLID LIPID PARTICLE SOLID LIPID NANOSPHERES (SLN) - Google Patents

Abstract

Medication vehicles have particles made of lipids, lipid-like (lipoid) materials or mixtures thereof, with a diameter from 10 nm to 10 mu m, that are solid at the ambient temperature. Because or their solid core, these medication vehicles allow active substances to be controllably released over a longer period, allow hydrophilic medicaments to be incorporated into the solid core and are relatively quickly decomposable, producing no toxic by-products.

Description

The invention relates to a drug carrier, the Disper sion in an aqueous medium, a process for its manufacture lung and its use. In particular, it is a Drug carrier made from lipid or lipoid particles.

In the field of active pharmaceutical ingredients is constantly on Carriers wanted, he a diverse type of application possible, d. H. be in a form that allows the each drug in the most appropriate way to the body by feed, e.g. B. intravenous, intraarthricular, intramuscular or subcutaneously.

For example, carriers made of solid microparticles are micro spheres and microcapsules known (average diameter in Mi range) as well as nanoparticles and nanocapsules (medium Diameter in the nanometer range). Micro and nanoparticles best hen from a solid polymer matrix. For micro and nanocapsules are liquid or solid phases of film-forming polishing envelops. Such particles consist of or have coatings from polymers such as polylactides (PLA), polylactide glycolides  (PLA / GA) or polyalkyl cyanoacrylates. Polylactide and poly However, lactide glycolide as a particle matrix and as coatings the disadvantage that they are degraded very slowly, d. H. the Dismantling takes weeks to months. This leads to multiple applications tion of a drug with this carrier to the polymer accumulator tion in the organism and possibly to toxic effects. Particles based on polymers such as polyalkyl cyanoacrylates are up to 80% in the body within 24 hours degraded, but toxic formaldehyde is released during degradation. For Production of the polymer particles must be used as a solvent for the Polymer, for example chlorinated hydrocarbons such as dichloromethane are used, which in turn are toxic (T.R. Tice and D.H. Lewis, Microencapsulation Process, U.S. Patent 4,389,330). Microparticles can also be due to their size lead to embolism during intravenous injection, so here apart from that. Another disadvantage of poly merpartchen is that when sterilizing in an autoclave Glass temperature is exceeded, so that it becomes an aggrega tion of the particles is coming. Such drug carriers or Arz This means that drugs cannot be sterilized in this way have to use the disadvantageous path of the radiation steri treatment.

Also known are fat emulses that can be used as drug carriers sions. Fat emulsions are oil-in-water emulsions in which the dispersed (inner) phase is liquid. In the literature such fat emulsions are also called "lipid microspheres" and highly disperse fat emulsions with a medium particle sizes in the nanometer range are also called "nanoemulsions" draws (H.G. Weder and M. Muetsch, Eur Pat. EP 90-8 10 436, June 1990). These fat emulsions consist of two liquids phases. Fat emulsions give way to incorporated drugs Dilution with body fluids (e.g. after injection into Blood) released relatively quickly. The t (50%) is in the range of 30 to 60 seconds, what with the high diffusion rate of Drugs in the relatively low-viscosity oil is correlated. To  In addition, the liquid dispersed phase of the fat emulsion NEN (= oil) in the organism completely within a few hours metabolized, resulting in rapid release also from extreme leads lipophilic substances from the oil. Due to the quick free Settlement can also lead to so-called active ingredient peaks in the plasma come, so that due to this short overdose toxi side effects are possible. In addition, the loss of active ingredient before reaching the target organ in the passive target Compared to liver and spleen macrophages relatively large.

By P. Eldem, P. Speiser and A. Hincal, Pharmaceutical Re search 8, 47-54 (1991) micropellets based on lipids are known, whose average diameter is in the micrometer range.

Drug carriers in which liposomes or Liposome-like or analogous substances such as niosomes an aqueous, liquid core of one or more phospho lipid double membranes are surrounded.

They are also sub-particulate or semi-particulate systems known in which substances with the help of solubilizers how surfactants are dissolved so far that micelles or mixed form micelles. This is no longer a Disper sions are already about solutions.

The invention is therefore based on the object of a medicament To provide fabric carrier, which is a dispersion of Particles can form in an aqueous medium, the part are solid and biodegradable at room temperature and also consist of components that have little or no Show toxicity. In the manufacture of the drug carrier Furthermore, no toxic auxiliaries such as dichloromethane or similar ones are needed. Furthermore, a method for the manufacture tion of this drug carrier can be made available.  

The object of the invention is achieved by a Dissolved drug carrier, the particles of lipid or lipid-like material (lipoid) or mixtures thereof, which have a diameter of 10 nm to 10 µm and at room temperature temperature are fixed.

Preferred embodiments of this drug carrier are counter stood the subclaims.

The drug carrier is at room temperature (i.e. about 20 ° C) solid particles with a size in the nanometer range rich. Such particles can be called "solid lipid nanospheres" (solid lipid nanosperes - SLN). These particles can be dispersed in an aqueous medium so that gives a solid / liquid dispersion. The particle size of the dis Peared phase ranges from <10 nm to less micrometers (approx. 10 µm). The average particle size (by knife determined by means of photon correlation spectroscopy) predominantly in the range from 100 nm to 1000 nm, in particular 200 up to 800 nm.

The SLN consist of lipids or lipid-like substances that are broken down by the organism like fat from food can. The breakdown of lipids is faster than the breakdown of synthetic polymers such as PLA, PLA / GA. Advantageously also arise during the breakdown or metabolism of Lipids are not toxic metabolites like particles on poly alkyl cyanoacrylate base is the case. In this regard, the Toxicology of parenteral nutrition since the 1950s used fat emulsions.

Since the SLN are solid lipid particles with corresponding high viscosity is the diffusion and release speed of an active substance included therein graces. So it is in contrast to fat emulsions with liquid dispersed phase possible, the setting of a controlled  to achieve th release over a longer period of time. On Due to the longer release time, the formation of plasma peaks of the respective active ingredient avoided, so that due to such side effects do not occur. Furthermore, the loss of active ingredient after application and before Reaching the respective target organ due to the delayed Release less than with fat emulsions in which the active substances are released comparatively quickly.

The active ingredient (s) are in the lipid or lipoid particles dissolved or dispersed. They can also on their surface be adsorbed. Due to the solid character can also hydrophilic active substances in the form of an aqueous active substance solution in the lipid or lipoid phase can be incorporated. After this Incorporation and subsequent dispersion of the obtained SLN in the aqueous dispersion medium creates a system W / F / W, d. H. Water in fat in water. The lipid core closes here the aqueous drug solution due to its solid aggregate it was better than comparable multiple emulsions water in oil in water (W / Ö / W) is possible.

Another advantage of the solid lipid nanospheres is that they are in the Contrary to particles of polymer in an autoclave sterile are capable of aggregation of the particles is coming. In this way, those with radiation sterilization associated disadvantages can be avoided.

In contrast to microparticles from the micrometer range, they are SLN due to their small particle size in the nanometer range can also be injected intravenously without any risk of embolism.

No toxic auxiliaries such as e.g. B. volatile chlorinated hydrocarbon solvents be set.  

The pharmaceutical carrier according to the invention can be in the following ways getting produced:

• 1. Disperse the inner phase (lipid or lipoid) in melted or softened state. The dispersion takes place above room temperature and can vary dene, for example the methods described below be effective.
• 2. Dispersion of the solid inner phase in the solid state. The solid phase is finely crushed and in water or dispersed in an aqueous medium.

The dispersed lipid or lipoid that is solid at room temperature The core was previously loaded with one or more drugs. This can be done in that the active ingredient in the lipid / Li poid is dissolved or dispersed, on its surface adsor is beer or in the form of an aqueous solution in the lipid / Li poid is dispersed.

As the dispersed phase, lipids and lipoids can be used broadly Senses used as individual compounds or as mixtures will. Examples include natural and synthetic Triglycerides or their mixtures, mono- and diglycerides all ne or in a mixture with each other or with z. B. triglycerides, natural and synthetic waxes, including fatty alcohols their esters and ethers as well as lipid peptides. In particular are synthetic mono-, di- and triglycerides as single substances or in a mixture (e.g. hard fat), glycerol trifatty acid ester (e.g. glycerol trilaurate, myristate, palmitate and stearate) and Waxes such as B. Cetyl palmitate and Cera alba (bleached wax, DAB 9) suitable.

If necessary to produce stable dispersions should be able to use dispersion stabilizing additives these to stabilize the particles in the form of pure substances  or used in the form of mixtures. As a stabilizer Possible substances are:

• a) surfactants, especially ethoxylated sorbitan fatty acid esters, Block polymers and block copolymers (such as poloxamers and Poloxamines), polyglycerol ethers and esters, lecithins ver of various origins (e.g. egg or soy lecithin), chemical modified lecithins (e.g. hydrogenated lecithin) as well Phospholipids and sphingolipids, mixtures of lecithins with phospholipids, sterols (e.g. cholesterol and cholesterol bovine derivatives and stigmasterol), esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols (e.g. Sucrose monostearate),
• b) sterically stabilizing substances such as poloxamers and pol oxamines (polyoxyethylene-polyoxypropylene block polymers), ethoxylated sorbitan fatty acid esters, ethoxylated mono- and Diglycerides, ethoxylated lipids and lipoids, ethoxylated Fatty alcohols or fatty acids and
• c) charge stabilizers or charge carriers such. B. Dicetyl phosphate, phosphatidylglycerol as well as saturated and unsaturated saturated fatty acids, sodium cholate, amino acids or peptisato such as sodium citrate (see J. S. Lucks, B.W. Müller, R.H. Müller, Int. J. Pharmaceutics 63: 183-188 (1990)).

As outer phase (continuous phase, dispersant) water or aqueous media are used. The aqueous me these can be non-isotonic or isotonic. As aqueous media come mixtures of water with one or more other components such as glycerin, mannose, Glucose, fructose, xylose, mannitol, sorbitol, xylitol or other Po lyols as well as electrolytes such as sodium chloride.

The SLN is usually produced by dispersing the inner phase (the lipid or lipoid), in the outer  Phase (water or aqueous medium) above room temperature (<20 ° C). The temperature is chosen so that the disper Yielding substance is in the liquid state or at least is in the softened state. With many lipids this occurs Dispersion at 70 to 80 ° C. The production takes place usually in two steps:

• 1. Make a predispersion, e.g. B. with a stirrer or a rotor-stator disperser (e.g. Ultra Turrax). If it is necessary to add one or more dispersion-stabilizing substances.
• 2. Subsequent dispersion at elevated pressure in one High pressure homogenizer (e.g. a gap homogenizer like APV Gaulin or French Press, a high-speed homogenizer sator like the microfluidizer) or by ultrasound (e.g. using ultrasound rods from Branson, Labsonic). All right dispersible systems, step 1 can be omitted.

The incorporation of the active ingredient (s) can be carried out in different ways Methods are done. Examples include:

• 1. Dissolve the active ingredient in the inner phase.
• 2. Dissolve the active ingredient in a mixture with the inner phase ed solvent and addition of this drug solution inner phase. Then, if necessary, the solution partially or completely removed.
• 3. Dispersion of the active ingredient in the inner phase (e.g. by Dispersing a solid or targeted precipitation).
• 4. Dissolving the active ingredient in the outer, aqueous phase (e.g. amphiphilic substances) and incorporation of the active ingredient in a particle stabilizing surfactant film during the Manufacturing.
• 5. Adsorption of the active ingredient on the particle surface.
• 6. Dissolve the active ingredient in the lipid / lipoid phase using a solubilizer (e.g. a block copolymer or  Sorbitan fatty acid ester), then dispersing the Lipid / lipoid phase for the preparation of the predispersion. The The active substance is then present in the SLN as a solid solution.
• 7. Incorporation of aqueous active ingredient solutions in the lipid / li poid phase and subsequent dispersion of the lipid / li poiden phase for the preparation of the predispersion, so that a System W / F / W arises, which is analogous to the multiple emulsions is.

The sterilization can be carried out according to the procedures in the Pharmacopoeias are described, e.g. B. by autoclaving (121 ° C, 2 bar, DAB 9) or according to other recognized procedures.

The fields of application for the drug carrier according to the invention The solid lipid nanospheres are diverse. Example it can be used for parenteral, enteral, pulmonary and topi medication (nasal, dermal, intraocular) and in body cavities fabric applications are used.

Parenteral administration is particularly important around:

• 1. Intravenous administration (targeting the liver, spleen and bone marrow, Particles circulating in the blood with controlled release drawing of active ingredients, e.g. B. peptide drugs, cytostatics, Immune stimulants, growth factors such as the colony stimula ting factor (leucocyte regulation) and the growth factor.
• 2. Intramuscular administration (depot forms for prolonged or long sustained release of active ingredients, e.g. B. Peptide Drugs or hormones).
• 3. Intraarthricular administration (e.g. for anti-inflammatory drugs and Imunsup pressiva for arthritis).
• 4. Intracavital administration (e.g. for cytostatics and peptide drugs substances for cancer forms in the peritoneum and in the pleural cavity) and
• 5. Subcutaneous administration (e.g. depot forms for cytostatics in skin cancer).

The enteral application forms are used in particular for

• 1. incorporation of lipid-soluble vitamins,
• 2. lymphatic adsorption (e.g. drug targeting by Cyto statics to the lymph nodes),
• 3. Presentation of antigens (e.g. oral immunization with Help of the Peyers plaques) and
• 4. Uptake of peptide drugs with the help of M cells.

The pulmonary forms of application come in particular from Be costume:

• 1. Aerosols, metered dose aerosols (spraying the aqueous SLN-Dis persion),
• 2. Instillation of the dispersion.

As a topical application are exemplary

• 1. dermatological drugs for the application of z. B. Corti koiden and antifungals,
• 2. Eye drops or eye gels, e.g. B. for β-blockers, but also
• 3. Cosmetics called analogous to liposomal preparations.

The invention is explained in more detail in the following examples.

example 1

10.0 g Cera Alba (bleached wax)
2.5 g poloxamer 188 (polyoxyethylene-polyoxypropylene block polymer)
0.1 g dicetyl phosphate
87.4 g water for injections

Cera alba and dicetyl phosphate were heated to 700 and with the also heated to 70 ° C solution of Poloxamer 188 in water mixed for injections. The mixture was made using of an Ultra Turrax predispersed at 70 ° C. The so obtained The predispersion was then tempered to 70 ° C.  APV Gaulin high pressure homogenizer (5 cycles with 500 bar). It became an SLN dispersion with a medium through received a knife of 216 nm. The polydispersity index as a measure for the width of the particle size distribution was 0.143 (PCS Photon correlation spectroscopy). All particles were smaller than 6.0 µm (measured with a Sympatek laser diffractometer).

Example 2

10.0 g cetyl palmitate
2.5 g poloxamer 188
87.5 g water for injections

The preparation was carried out as described in Example 1. The mean diameter was 215 nm, the polydispersity index 0.131 (PCS data). All particles were smaller than 4.2 µm (La diffractometer).

Example 3

10.0 g cetyl palmitate
2.5 g Lipoid S 75 (soy lecithin with 75% phosphatidylcholine)
0.1 g dicetyl phosphate
87.4 g water for injections

The preparation was carried out as described in Example 1, each however, Lipoid S 75 was dispersed in the heated lipid phase. The mean diameter was 183 nm, the polydispersity index 0.133 (PCS data). All particles were smaller than 8.6 µm (Laser diffractometer).

Example 4

10.5 g glycerol trilaurate (Dynasan®112)
2.5 g poloxamer 188
87.5 g water for injections

The preparation was carried out as described in Example 1. The mean diameter was 199 nm, the polydispersity index 0.180 (PCS data). All particles were smaller than 7.2 µm (La diffractometer).

Example 5

10.0 g cetyl palmitate
2.5 g poloxamer 188
0.5 g dicetyl phosphate
87.0 g water for injections

The preparation was carried out as described in Example 1. The Characteristics before and after autoclaving prove the application availability of the sterilization method;

Example 6

0.25 g of tetracaine base was used as the model drug in the recipe 5 incorporated.

The preparation was carried out as described in Example 1. The mean diameter was 218 nm, the polydispersity index 0.186 (PCS data). All particles were smaller than 10.2 µm (laser diffractometer).
The drug load was 92.8%
The particles can also be lyophilized or spray dried using active substances sensitive to hydrolysis.

The invention also includes the process for the preparation of the described drug carrier and its use for Application of active pharmaceutical ingredients.

Overall, the solid lipid nanospheres combine the Advantages of polymer nanoparticles (solid core, controllable Release over a longer period of time, training possible for hydrophilic drugs) with the advantages of parente oral fat emulsions (relatively quick degradability, low or no toxicity, production on an industrial scale techniques established in emulsion production, easy Sterilization by autoclaving) bypassing the disadvantages of nanoparticles (slow degradation in vivo or toxic Breakdown products, lack of scaling-up possibility in the product tion) and the disadvantages of fat emulsions (e.g. very fast Metabolism, very fast drug release).

Claims (16)

1. Drug carrier, the particles of lipid, lipid-like (Lipoid) material or mixtures comprising a through have a diameter of 10 nm to 10 µm and at room temperature are firm. 2. Carrier according to claim 1, characterized in that the Particles have an average diameter of 100 to 1000 nm exhibit. 3. Carrier according to claim 1 or 2, characterized in that the particle material mono-, di- and triglycerides, fatty alcohol hole, their esters or ethers, waxes and lipid peptides as well Mixtures thereof. 4. Carrier according to one of claims 1 to 3, characterized notes that the triglyceride glycerol trilaurate, myristate, palmitate and stearate, the fatty alcohol cetyl and stearyl alcohol and the wax cetyl palmitate and bleached beech include wax. 5. Carrier according to one of claims 1 to 4, characterized records that he also one or more dispersionssta bilizing substances. 6. Carrier according to claim 5, characterized in that the sta bilizing substances compounds from the series of pol oxamers, poloxamines, ethoxylated mono- and diglycerides, ethoxylated lipids and lipoids, ethoxylated fatty alcohols and alkylphenols, ethoxylated fatty acid esters, polyglycine rinethers and esters, lecithins, esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols, Phospholipids and sphingolipids, sterols, their esters or Include ethers and mixtures of these compounds.   7. Carrier according to claim 5 or 6, characterized in that the stabilizing substance egg lecithin, soy lecithin or hydrogenated lecithin, their mixtures or mixtures of one or both lecithins with one or more phos pholipid components, cholesterol, cholesterol palmitate, stig masterin or other sterols. 8. Carrier according to one of the preceding claims, characterized characterized that he also around charge stabilizers sums up. 9. A carrier according to claim 8, characterized in that the Charge stabilizers dicetyl phosphate, phosphatidyl glycerol, saturated or unsaturated fatty acids, sodium cholate, Include peptizers or amino acids. 10. Carrier according to one of the preceding claims, characterized ge indicates that the particles are in distilled water or an aqueous medium with additives from electrolytes, mono- and disaccharides, polyols or mixtures thereof are greeded. 11. A carrier according to claim 10, characterized in that the Additives sodium chloride, mannose, glucose, fructose, xylose, Mannitol, sorbitol, xylitol and glycerin include. 12. Carrier according to one of the preceding claims, characterized ge indicates that the particles are lyophilized or sprayed are drying. 13. Carrier according to one of the preceding claims, characterized ge indicates that it has no, one or more active substances includes. 14. A carrier according to claim 13, characterized in that the or the active ingredients dissolved or dispersed in the particles  are adsorbed on the surface or as aqueous Solution are dispersed in the particles. 15. A method for producing the drug carrier according to An saying 1, characterized in that either the inner Phase (the lipid or lipoid) in melted or softened state in the dispersant (water or aqueous Medium) is dispersed or the inner phase in solid State in which the solid phase is finely crushed in which Dispersant is dispersed. 16. Use of the drug carrier according to claim 1 for Ap application of active pharmaceutical ingredients.